Functions of Hormones and Their Regulation

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Functions of hormones and their regulation

The word hormone is derived from the Greekhormao meaning 'I excite or arouse'.Hormones communicate this effect by their unique chemical structures recognized by

specific receptors on their target cells, by their patterns of secretion and their

concentrations in the general or localized circulation. The major hormones discussed in thisbook are listed inBox 1.1.

Their functions can be broadly grouped into several categories: reproduction and sexual

differentiation; development and growth; maintenance of the internal environment; and

regulation of metabolism and nutrient supply. A single hormone may affect more than one

of these functions and each function may be controlled by several hormones. For example,thyroid hormone is essential in development as well as many aspects of homeostasis and

metabolism, whilst glucocorticoids, such as cortisol, are important both in growth and

nutrient supply and are also modulators of immune function. The roles several hormonesplay in one function is exemplified by the control of blood glucose which involves the

pancreatic peptide insulin and its counter regulatory hormone, glucagon, as well as cortisol,growth hormone and epinephrine. Hormones act in concert and thus, an abnormality in acontrolled variable, such as blood glucose concentration may result from defects in the

control of any one of several hormones.

The secretion of hormones is subject to negative feedback control, and there are several

ways by which this is achieved (Box 1.2). Feedback loops may involve the hypothalamo-pituitary axis that detects changes in the concentration of hormones secreted by peripheral

endocrine glands or a single gland may both sense and respond to changes in a controlled

variable. The integration of feedback loops involving several hormones may be complex.Disturbances in feedback loops are clinically important and their significance in diagnosis

is pivotal.1.1. Classification by structure of the major human hormones*

Hormones Peptide/protein Steroid Amino acid or fatty

acid derived

Hypothalamic

hormones

Thyrotrophin releasing

hormone (TRH)

Corticotrophin releasing

hormone (CRH)

Arginine vasopressin

(AVP)

Gonadotrophin releasing

hormone (GnRH)

Growth hormonereleasing hormone

(GHRH)

Somatostatin

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Prolactin relasing factor

(PRF)

Dopamine

Anterior pituitary

hormones

Thyroid-stimulating

hormone (TSH)

Adrenocorticotrophichormone (ACTH)

Luteinizing hormone

(LH)

Follicle-stimulatinghormone (FSH)

Somatotrophin/growth

hormone (GH)

Prolactin (PRL)

Melanocyte-stimulating

hormone (MSH)

Posterior pituitaryhormones

Oxytocin

Arginine vasopressin

Thyroid hormones Thyroxine (T4)

Triiodothyronine(T3)

Pancreatic

hormones

Insulin

Glucagon

Somatostatin

Pancreatic polypeptide

Calcium regulatinghormones

Parathyroid hormone(PTH)

1,25-dihydroxyvitamin D

Calcitonin (CT)

Parathyroid hormone-

related peptide (PTHrp)

Adrenal cortical

steroids

Cortisol

Aldosterone

Dehydroepiandrosterone

Adrenal medullaryhormones

Epinephrine

Norepinephrine

Male reproductivehormones

Inhibin Testosterone

Dihydrotestosterone

Female Inhibin Estradiol

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reproductive

hormones

Oxytocin Progesterone

Human chorionic

gonadotropin (hCG)

Human chorionicsomatotrophin

Plasma volume and

sodium regulating

hormones

Atrial natriuretic peptide

(ANP)

Arginine vasopressin

Renin/angiotensin Aldosterone

Cardiovascular

hormones

Atrial natriuretic peptide

(ANP)

Nitric oxide

Endothelins

ErythropoietinBradykinin

Pineal hormones Melatonin

Serotonin

Growth factors or

cytokines

Insulin-like growth

factors (IGFs)

Epidermal growth factor

(EGF)

Interleukins (ILs)

Tumor necrosis factor

(TNF)-

Eicosanoids Prostaglandins

Thromboxanes

Prostacyclin

Leucotrienes

Lipoxins

1.4. Chemical structures of the three major classes of human hormones

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Other hormones include those derived from tryptophan (serotonin and melatonin,Boxes

7.33 and8.12) and those derived from fatty acids (eicosanoids,Box 8.8).

Transport of hormones in the circulation and their half-lives

Steroid and thyroid hormones are less soluble in aqueous solution than protein and peptidehormones and over 90% circulate in blood as complexes bound to specific plasmaglobulins or albumin. Bound and free hormones are in equilibrium (Box 8.28). More

recently, binding proteins for several protein and peptide hormones (e.g. CRH, GH) as well

as growth factors (e.g. IGF) have also been identified.

It is generally accepted that it is the unbound or free hormone that is biologically active andthat hormone binding delays metabolism and provides a circulating reservoir of hormones.

More recently, it has been suggested that the specific binding globulins are not just passive

transporters but may interact with membrane receptors and that hormone binding to theglobulins initiates a signal transduction pathway.

Most binding proteins are synthesized in the liver and alterations in the serum

concentrations of these proteins alter total serum concentrations of a hormone but may

have much less effect on the concentrations of free hormone. As a result, situations mayarise in which assays of total hormone concentrations do not reflect changes in free

hormone concentrations. Measurement of biologically relevant free hormone

concentrations (Box 3.30), however, is generally more difficult than measuring totalhormone concentrations.

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The rates of metabolism of hormones in the circulation vary but generally speaking the half

life (t1/2) of catecholamines from the adrenal medulla is in the order of seconds, minutes for

protein and peptide hormones and hours for steroid and thyroid hormones

Hormone receptors - cell surface

Proteins and peptides are water soluble and, hence, do not diffuse across hydrophobic lipid

cell membranes. Thus, parts of their receptors lie extracellularly (where hormone-receptorinteractions occur) and they couple with intracellular signal transducing molecules by

traversing the cell membrane. The majority of classical protein and peptide hormone

receptors are the G-protein linked receptors (Box 1.8) and these may either have arelatively short extracellular amino terminal domain (e.g. epinephrine, GnRH) or a much

longer extracellular domain (e.g. TSH, LH, PTH). Extracellular hormone-receptor

interactions induce dissociation of the associated intracellular trimeric G protein (Box

1.10). This may either open ion channels in the membrane or activate a membrane boundenzyme that stimulates (or inhibits) the production of a second messenger such as cyclic

AMP or diacylglycerol and inositol trisphosphate (Box 1.10). These second messengers

then activate serine/threonine kinases (Box 1.9) or phosphatases.

Activation of these protein kinases may have three consequences. It can lead to alterations

in specific cytosolic enzyme activity, activation of nuclear transcription factors (Boxes 1.10

and 1.13) or initiation of a cascade of subsequent phosphorylations on the serine or

threonine residues of protein kinases that can also regulate transcription (Box 1.10).

The second most common type of cell surface receptors is that used in the signalling of

insulin, growth hormone, prolactin, most growth factors and cytokines. This type is atransmembrane receptor with either inherent protein tyrosine kinase activity on theintracellular domain (e.g. insulin and growth factor receptors) or associated intracellular

molecules (Box 1.9) that have this activity (e.g. receptors for growth hormone, prolactin

and cytokines). Binding of the hormone or growth factor to the extracellular domain results

in receptor dimerization with an adjacent receptor initiating either autophosphosphorylation(Box 1.10) or phosphorylation of an associated enzyme. Subsequently, there are similar

signal transduction events to those described above that involve both cytoplasmic and

nuclear events.

Signal transduction pathways for cell surface receptors

These are complex processes and unfortunately dogged by terminology that is confusing

and not always logical - a legacy from the periodic discovery of intracellular factors that

were subsequently assembled into a relatively complete sequence of signal tranductionprocesses. It is not in the scope of this book to pursue all the molecular events but a broad

outline is pertinent to understanding hormone action and genetic mutations that can cause

endocrine disorders.

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Receptors that have inherent tyrosine kinase activity bind molecules that have a specific

SH2 domain (src homology domain). In turn, another accessory protein may be activated

such as SOS (son-of-sevenless). This can activate a monomeric G-protein known as Rasthat essentially acts as a signal transduction switch. Its activation can lead to

phosphorylation of Raf, MEK and eventually to mitogen activated protein kinase (MAPK)

which can initiate transcription (termed the MEK-MAPK pathway).

Receptors for GH, prolactin, erythropoietin, insulin and a variety of cytokines and growthfactors do not have inherent protein kinase activity but are associated with a protein that

has tyrosine kinase activity. One of these proteins, known as JAK (just anotherkinase)

may activate downstream effectors that include the STAT proteins - the JAK-STATpathway. Binding of insulin to its receptor induces phosphorylation of insulin receptor

substrate proteins (IRS) which activates further signal transduction pathways including

activation of nuclear transcription factorB (NF-B). In essence, there is a cascade ofprotein phosphorylations that ultimately end in the nucleus to induce transcription.

The transcription factor targets for kinases that are activated by protein and peptidehormones include c-jun and c-fos which make up the heterodimeric AP-1 complex, the

serum response factor (often targeted by the MAP kinase dependent pathway), and nuclearCREB-P (cAMP response element binding protein) which is phosphorylated by protein

kinase A and enhances transcriptional activity of closely positioned promoters

.8. The two main classes of protein and peptide hormone receptors

G-protein linked receptors that frequently activate serine/threonine kinases through secondmessengers such as cAMP, diacylglycerol, calmodulin

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Receptors with inherent tyrosine kinase activity or associated with intracellular molecules

possessing tyrosine kinase activity. Some intracellular kinases are attached to the

membrane.

.9. Kinases associated with signal transduction mechanisms of protein and peptidehormone receptors

Some receptors possess inherent tyrosine kinase activity or are associated with intracellular

molecules (e.g. JAK) that are activated upon hormone binding. G-protein linked receptorsactivate intracellular serine/threonine kinases via second messengers. The location of

kinase activity is indicated by open (white) frames

1.10. Signal transduction pathways and transcriptional (nuclear) actions of protein

and peptide hormones

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Protein and peptide hormones can activate a number of transcriptional factors by

phosphorylation. This may involve the MEK-MAP pathway (serine-threonine kinases) or

direct activation of transcription factors by protein kinase (PK) A, PKC or the Ca2+-calmodulin activated CaM protein kinase (not shown).

Abbreviations: EGFR, epidermal growth hormone receptor; AC, adenylate cyclase; PLC,

phospholipase; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-

trisphosphate; DAG, diacylglycerol; Shc/Grb, accessory proteins with SH2 (src homology)

domains; SOS, son-of-sevenless; Ras, monomeric

Hormone receptors - intracellular

Steroid and thyroid hormones are lipophilic and readily diffuse across cell membranes.

Their receptors are typically intracellular and are classified according to their cellularlocation, their dimerization and the sequences of DNA to which they bind. There is a large

family of steroid receptors, all of which are transcription factors. They bind to DNA and

with other transcription factors initiate RNA synthesis. Whilst receptors for the majorsteroid hormones have been identified (Box 1.11) other structurally similar molecules have

been identified though their ligands have not. These have been termed orphan receptors.

The characteristic single polypeptide chain is structurally and functionally divided into six

domains. At the amino terminus are the A/B domains that are variable both in sequence andlength. The C domain, also called the DNA binding domain (DBD), is a highly conserved

sequence across all steroid receptors and is characterized by possessing two zinc fingers

which readily slot into the helix of the DNA molecule. The D domain is thought torepresent a hinge region in the molecule whilst E represents the ligand binding domain and

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F a variable region in the carboxyl terminus. This end of the molecule is also the region

where the heat shock proteins (hsps) are bound and where dimerization occurs.

Receptors that exist predominantly in the cytoplasm are classified as Type 1 receptors andthese include the glucocorticoid, mineralocorticoid, androgen and progesterone receptors.

They are bound to heat shock proteins (e.g. hsp 90, hsp70 and hsp 56). Upon steroidbinding the hsp complex is released and the receptor forms a dimer with another identical

receptor (Boxes 3.9 and5.7). The homodimer translocates to the nucleus where it binds to aspecific base sequence on the DNA. The estrogen receptor is also associated with hsps and

whilst this receptor shuttles between the nucleus and cytoplasm, most are confined to the

nuclear compartment. Type 2 receptors are typically located in the nucleus and may bebound to DNA. They characteristically form heterodimers (e.g. thyroid hormone receptor

and retinoid X receptor) or may initiate transcription as monomers upon ligand binding.

The specific amino acid sequence of the zinc fingers in the DNA binding domain is

important for determining the bases in the DNA helix to which the receptor binds and, thus,

the specificity of the transcriptional activity of the receptor. This is determined throughwhat is called the recognition helix that lies at the end of the first zinc finger and part of the

amino acid sequence between the two zinc fingers. Amino acids in the second zinc fingermake specific contacts with the phosphate backbone of the DNA.

Type 1 receptors recognize a base sequence AGAACA whilst Type 2 receptors and the

estrogen receptors recognize a base sequence AGGTCA. These are known as hormone

response elements on the DNA and can be further defined as a glucocorticoid responseelement (GRE) or estrogen response element (ERE), respectively (Box 1.12). These,

however, are half-site specificities of hormone receptors; the other half-site forms an

inverted palindrome, as recognized by Type 1 and the estrogen receptors, or by a direct

repeat of bases with variable number of bases between the half-site specificity. These aregenerally recognized by thyroid hormones, vitamin D, and retinoid receptors. The other

way in which steroid hormones can alter transcription is not via interaction with a GRE orERE on the DNA but by binding to and activating/repressing other transcription factors

that recognize a particular site on DNA (Box 1.13).

Many steroids and thyroid hormones can stimulate rapid responses in target cells that are

clearly non-genomic and may be explained by interaction with cell surface receptors. Suchreceptors may initiate the opening of ion channels or activate classical second messenger

systems. The difficulty of isolating such receptors has hampered their investigation but it is

clear that steroids exert membrane effe.12. Steroid receptors, zinc fingers and DNA

binding

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Generalized structure of all steroid hormone receptors showing the different domains,location of the zinc fingers and the regions of the receptor responsible for transcriptional

activity (TAF).

Two-dimensional structure of the zinc fingers of the DNA binding domain (DBD) in a

single receptor. I, II and III indicate the helical regions of the DBD. The first helix contains

the P box which determines the specificity of the DNA binding. The 3 amino acids thatdetermine whether the receptor will combine with a glucocorticoid response element

(GRE) or an estrogen response element (ERE) on the DNA are indicated. Arrows indicatethe different amino acids that convert GRE specificity to ERE specificity. Amino acidsshown as solid circles indicate those that are important for dimerization of two receptors.

Diagram showing dimerization of two receptors and helix I of each receptor slotting intothe helix of the DNA. The base sequences of the ERE and GRE are shown plus the

palindromic sequence. An example of a direct repeat sequence is also shown

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cts. 1.13. Signal transduction pathways of a peptide hormone and a steroidhormone that control gene expression by activating or inhibiting the activity of the

transcription factor, nuclear factor- B (NF- B)

Protein kinase C (PKC), activated by a peptide hormone via the inositol pathway,

releases the transcription factor, NF-B from its inhibitory subunit throughphosphorylation. NF-B moves into the nucleus where, along with other transcriptionfactors (TF), initiates transcription.

The binding of an anti-inflammatory glucocortocoid to the glucocorticoid receptor (GR)

induces release of the heat shock proteins and the hormone/receptor complex translocates

to the nucleus. It binds with NF-B preventing its transcriptional activity for pro-

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inflammatory proteins such as interleukin-6 (IL-6). This forms part of the anti-

inflammatory effects of glucocorticoids.

Hormone receptor regulation

Receptor regulation is an important part of endocrine function and this occurs through upor down-regulation of the number of receptors and by desensitization of the receptors. This

occurs by increasing or decreasing receptor synthesis, by internalization of membranereceptors after ligand binding, or by uncoupling of the receptor from its signal transduction

pathway (desensitization). The latter usually involves phosphorylation of the receptor.

Some hormones may regulate their own receptors (homologous regulation) such as GnRH

on the pituitary gonadotrophs whilst other receptors are regulated by other hormones(heterologous regulation) e.g. estrogen regulating oxytocin receptors.

Interaction between hormones and their receptors depends on the number of receptors, the

concentration of circulating hormone and the affinity of the hormone for the receptor. The

latter is defined as the concentration of a hormone at which half the total number ofreceptors is occupied (Box 1.14) and the higher the affinity the lower the concentration of

hormone required. Generally speaking the affinity of hormone receptors does not change

and thus the biological response depends on the number of receptors and the concentrationof hormone.

Usually less than 5% of hormone receptors are occupied at any one time and maximum

biological responses are achieved when only a fraction of the total number of receptors are

occupied. Thus, it might be questioned why a small reduction in receptor number or achange in hormone concentration should make much difference to the overall biological

response. This is governed by the law of mass action. If receptor numbers are reduced then

the chances of a hormone binding to a receptor are decreased. Thus, a higher concentrationof hormone is required to achieve a similar receptor occupancy. A similar argument may be

applied when hormone concentrations are reduced. Together these two parameters are

important in determining the target cell's response to a hormone despite low occupancy of

receptors (Box 1.14). Neuroendocrine interactions

All endocrine glands are innervated by autonomic nerves and these may either directly

control their endocrine function and/or regulate blood flow (and hence function) within thegland. Hormones, in turn, may affect central nervous system functions such as mood,

anxiety and behavior.

Neurosecretory cells (Box 1.3) may directly convert a neural signal into a hormonal signal.

In other words they act as transducers converting electrical energy into chemical energy.Thus, activation of neurosecretory cells leads to secretion of a hormone into the circulation.

These neurosecretory cells include: those that secrete hypothalamic releasing and inhibiting

hormones controlling TSH, ACTH, LH and FSH release from the anterior pituitary gland;the hypothalamic neurons the axon terminals of which secrete oxytocin and vasopressin

from the posterior pituitary gland; the chromaffin cells of the adrenal medulla

(embryologically modified neurons) that secrete epinephrine and norepinephrine into the

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general circulation. The significance of these neurosecretory cells is that they allow the

endocrine system to integrate and respond to changes in the external environment. Thus,

for example, the CRH-ACTH-cortisol axis can be activated by stress generated fromexternal cues as is oxytocin secretion by a suckling baby. The recent discovery that the

nervous system itself can synthesize neurosteroids has added new dimensions to the

concept of neuroendocrine integration. With regard to endocrine functionper se, thesignificance of these discoveries remains to be elucidated.

Hormones and the immune system

Since the discovery that surgical ablation of the pituitary gland caused atrophy of the

thymus gland, experimental evidence from animal studies has indicated that there is acomplex network of interactions between these two systems. The thymus gland, which is

essential for orchestrating immune responses, has two regions - one in which T cell

precursors from bone marrow mature and the other that secretes thymic hormones (Box1.15). The physiological role of thymic hormones is not clear but they are postulated to

promote T cell maturation (Box 1.15).

The immune system can be considered a sensory system as it responds to stimuli such as

bacteria, viruses, tumors and other antigens. When stimulated, cell-mediated or humoralimmune responses are activated and this information is sent to the hypothalamus (via the

circumventricular organs) by cytokines and peptide hormones secreted from cells of the

immune system. In addition neural and non-neural cells in the brain also synthesizecytokines. The neuroendocrine system responds to these signals which, in many ways, may

be considered a stress response.

Both cytokines and thymic hormones may influence the release of hypothalamic

neurohormones and, hence, pituitary secretions; overall, immune activation is stimulatoryto the release of pituitary hormones (Box 1.16). There is also evidence that cytokines act

directly on endocrine glands such as the pituitary, thyroid, pancreas, adrenals and gonads

and alter their secretions. Pituitary hormones and the secretions of their peripheral targetendocrine glands may modulate immune function. Thus, for example,

ACTH/glucocorticoids are immunosuppressants as are progesterone and testosterone whilst

the action of estrogens is both stimulatory and inhibitory. GH and prolactin may alsopotentiate immune responses through a variety of effects and can stimulate growth and

activity of the thymus gland (Box 1.16).

Thymic hormones and immunomodulators may alter endocrine function and hormones may

modulate immune responses. Cross-talk between the systems also occurs because immunecells release peptides that are identical to those produced by the hypothalamus and pituitary

gland. They are released in response to stimulation from both antigens and hypothalamic

hormones. For example, immune cells release ACTH that can stimulate the release of

glucocorticoids and thus, to some extent over-ride the negative feedback effects of stress-induced increases in cortisol secretion on the hypothalamo-pituitary axis. Furthermore,

interleukin-1, released by macrophages, stimulates the secretion of hypothalamic CRH

release. Thus, high cortisol secretion rates are maintained. It should be noted, however, that

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recent studies on knock-out mice suggest that many hormones are not essential

immunomodulators but act as stress-modulating hormones in most cells, including those of

the immune system.

Autoimmunity

The primary role of the immune system is defensive and it is required to distinguish normal

self- components from those of foreign invaders or pathogens. Tolerization is a complex

process and loss of tolerance may lead to inappropriate activation of the immune systemcausing tissue destruction and autoimmune disease. Theoretically all tissues in the body

should be equally frequent targets for autoimmune destruction but endocrine tissues appear

more susceptible.

The factors that predispose to the development of autommunity are not completelyunderstood but there is clearly a genetic association and the most clearly established is that

of the genotype of the major histocompatability complex (MHC). This is a set of linked

genes coding for glycoproteins through which monocytes/dendritic cells and Blymphocytes present antigens to receptor molecules on T cells (Box 1.15). In humans, the

MHC is referred to as human leukocyte antigen (HLA) and the HLA region, located on the

short arm of chromosome 6, contains at least 50 genes extending over 4 million base pairs.

Whilst genetic linkages in the HLA complex and autoimmune disease have beenestablished, how they contribute to the pathogenesis of autoimmun-ity remains unknown.

The strongest linkage has been with certain HLA-DQ -chains (specifically the presence ofaspartic acid at position 57). Since this is involved in the peptide binding cleft of themolecule it has been thought that it involves an error in antigen presentation. However, the

exact mechanism remains uncertain.

The same can be said of the role of T and B cells in the pathogenesis of autoimmunity. T

cells maturing in the thymus gland can certainly be deleted to prevent autoimmune disease(if they react too strongly to the MHC complex) and the same may be true of B cells.

Whatever the mechanism of autoimmunity, there is no simple explanation of the sequence

of events. Human autoimmune diseases only become clinically evident after considerabletissue damage or disruption has occurred and this makes it difficult to establish the course

of pathogenesis and particularly its initiation. There are clearly familial traits of inheritance

that can predispose to autoimmune disease, but the fact that only 30 50% of identical twinsdevelop the same autoimmune disease suggests that other factors are involved, including

those of the environment

1.15. Simplified overview of the organization of the immune system

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*The interaction of antigen-presenting cells (these include monocytes, macrophages and

dendritic cells) that present peptide antigens bound to class II MHC molecules to T cellsthat express CD4 co-receptors is shown in detail (see text).

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Hormones, growth promotion and malignancy

Many hormones and growth factors promote growth in fetal and post-natal life and, thus, it

has been suggested that they may also promote tumorigenesis. Whilst it is known that

many growth factors such as the insulin-like growth factors induce proliferation in bothnormal and malignant cells, their precise role in the development of malignancy is

unknown. There is, however, substantial evidence that human cancers do not result from a

single genetic event but from stepwise genetic changes that result in the activation of proto-oncogenes and the inactivation of so-called antioncogenes or tumor suppressor genes.

Proto-oncogenes are cellular (c) genes that are thought to have been captured and

recombined into transforming (viral) oncogenes (v) by certain retroviruses. Such genes

code for growth factors or their receptors that are homologous or identical to the proteinscoded by the normal cellular proto-oncogenes. For example c-erb B-1 codes for the EGF

receptor whilst its transformed oncogene v-erb B-1 codes for a truncated form of the EGF

receptor. Similarly c-src which codes for the IGF-1 receptor, can be tranformed into v-srcthat codes for a modified protein kinase. These receptors may be constitutively active, not

requiring the presence of a ligand. Similarly, genes for the growth factors, e.g. c-sis and c-

intthat code for platelet derived growth factor beta chain and basic fibroblast factor,

respectively, can be transformed and inappropriately expressed in tumor cells. The

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importance of growth factors and their receptors in the phenotype of many malignancies

makes them potential therapeutic targets.

Sex steroids are well known to cause or promote tumor growth in target tissues such asbreast, endometrium and prostate. Thyroid, testicular and ovarian tumors, occurring in

glands controlled by the trophic hormones TSH, LH and FSH may also be putativelyincluded in the list of endocrine-dependent cancers. Two final points need to be noted with

regard to growth factors, hormones and cancer. First, transformed cells may produceprotein and peptide hormones providing an ectopic source of a hormone that is not under

the regulatory feedback control of normally functioning endocrine glands. Second, tumors

or their treatment may cause long-term endocrine complications.

Genes, mutations and endocrine function

It has been said that the practice of clinical genetics has always been facilitated by the fact

that those carrying mutations always present to clinicians. Clearly this is not always true as

some mutations in crucially important genes will be uniformly fatal in utero and neverpresent clinically. The genetic study of such, albeit rare, patients presenting clinically has

provided an enormous amount of knowledge in endocrinology. When such mutations are in

the germ line, such conditions present as familial diseases. Novel somatic mutations maypresent with expression only within specific tissues. Clinical examples of the effects of

mutations are given in the text where appropriate.

Animal models (predominantly rodent) have also provided an enormous insight into

endocrine diseases. Some of these mouse and rat strains were the result of naturallyoccurring mutations. More recently genes have been experimentally inserted (transgenic) or

deleted (knockout) in mice and these animal models have provided considerable scientific

knowledge. Not all the insights gained from such approaches can be directly extrapolatedto the human and it has to be borne in mind that redundancy within endocrine and

biochemical systems means that the phenotypic results of such experiments are not always

as straightforward as expected.

As the human genome project reaches its target, it is to be hoped that the knowledge gainedmay be used to further knowledge of the causes of the polygenic disorders so common in

endocrinology such as obesity, diabetes mellitus and autoimmune diseases

Clinical evaluation of endocrine disorders

It is important to emphasize the oxymoron that patients are bioassays of their circulating

hormone concentrations. This is seen repeatedly in the clinical cases that form the

springboards for the scientific knowledge throughout this book. Generally, in

endocrinology patients come to attention for only two reasons - because of excess hormoneaction or through its lack. Each has a number of possible causes.

Excessive amounts of a hormone may be secreted by tumors. The normal feedback loop

may be reset so that the amount of hormone secreted is abnormal only in the context of the

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concentration of the variable that it controls. In some cases, the relevant hormone may, in

fact, be absent but its receptor may be constitutively activated. On the other hand, there

may be a non-physiological stimulator of the receptor such as an antibody. The post-receptor signal transduction pathway may contain an abnormal protein that signals

continued receptor occupancy. Finally, excess hormone may be ingested accidentally,

deliberately or, indeed, therapeutically.

A lack of hormone effect may result from a lack of the hormone however caused (e.g.genetic deletion, damage to the endocrine gland, lack of a synthetic enzyme) or from the

production of a biologically inactive hormone. The hormone receptor (or the down-stream

signalling pathways) may be structurally abnormal and inactive leading to hormoneresistance.

The pace of progress in endocrinology has always been dictated by the development of

assays to measure the hormones. By and large, clinical endocrinology is limited to the

measurement of hormone concentrations in venous serum or body fluids such as urine or

saliva. Interpretation of the results of these assays should always take into account threefactors - the clinical features of the patient, the concentration of the variable regulated by

the hormone, and the concentration of other hormones in the feedback loop. For example, aserum insulin concentration can only be interpreted in light of the simultaneous glucose

concentration and correct interpretation of thyroid, adrenal or gonadal hormone

concentrations requires in many cases the results of the appropriate pituitary hormoneconcentrations. Tests of the feedback loops may be used; in general, in situations in which

hormone concentrations are expected to be high, suppression tests are used and in those in

which low concentrations are expected stimulation tests are used.

The practice of clinical endocrinology, like all branches of medicine, has been greatly

facilitated by the technological progress in imaging techniques, for example MR and CTscanning. It has also been aided by the exquisite specificity of the biochemistry of

individual tissues. Thus, radioactive iodine has been used for over 50 years to image thethyroid gland whilst recent techniques allow the use of radiolabeled agents such as

metaiodobenzylguanidine (MIBG) or radio-labeled somatostatin analogs to visualize

biologically active endocrine tissues. Examples of these and other techniques are given in

appropriate clinical settings